APOBEC3 degradation is the primary function of HIV-1 Vif determining virion infectivity in the myeloid cell line THP-1

Author:

Ikeda Terumasa1ORCID,Shimizu Ryo12,Nasser Hesham13,Carpenter Michael A.45,Cheng Adam Z.67ORCID,Brown William L.67,Sauter Daniel8ORCID,Harris Reuben S.45ORCID

Affiliation:

1. Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto, Japan

2. Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan

3. Department of Clinical Pathology, Faculty of Medicine, Suez Canal University , Ismailia, Egypt

4. Department of Biochemistry and Structural Biology, University of Texas Health San Antonio , San Antonio, Texas, USA

5. Howard Hughes Medical Institute, University of Texas Health San Antonio , San Antonio, Texas, USA

6. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota , Minneapolis, Minnesota, USA

7. Institute for Molecular Virology, University of Minnesota , Minneapolis, Minnesota, USA

8. Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen , Tübingen, Germany

Abstract

ABSTRACT HIV-1 must overcome multiple innate antiviral mechanisms to replicate in CD4 + T lymphocytes and macrophages. Previous studies have demonstrated that the apolipoprotein B mRNA editing enzyme polypeptide-like 3 (APOBEC3, A3) family of proteins (at least A3D, A3F, A3G, and stable A3H haplotypes) contribute to HIV-1 restriction in CD4 + T lymphocytes. Virus-encoded virion infectivity factor (Vif) counteracts this antiviral activity by degrading A3 enzymes allowing HIV-1 replication in infected cells. In addition to A3 proteins, Vif also targets other cellular proteins in CD4 + T lymphocytes, including PPP2R5 proteins. However, whether Vif primarily degrades only A3 proteins during viral replication is currently unknown. Herein, we describe the development and characterization of A3F -, A3F/A3G -, and A3A -to- A3G -null THP-1 cells. In comparison to Vif-proficient HIV-1, Vif-deficient viruses have substantially reduced infectivity in parental and A3F -null THP-1 cells, and a more modest decrease in infectivity in A3F/A3G -null cells. Remarkably, disruption of A3A–A3G protein expression completely restores the infectivity of Vif-deficient viruses in THP-1 cells. These results indicate that the primary function of Vif during infectious HIV-1 production from THP-1 cells is the targeting and degradation of A3 enzymes. IMPORTANCE HIV-1 Vif neutralizes the HIV-1 restriction activity of A3 proteins. However, it is currently unclear whether Vif has additional essential cellular targets. To address this question, we disrupted A 3 A to A 3 G genes in the THP-1 myeloid cell line using CRISPR and compared the infectivity of wild-type HIV-1 and Vif mutants with the selective A3 neutralization activities. Our results demonstrate that the infectivity of Vif-deficient HIV-1 and the other Vif mutants is fully restored by ablating the expression of cellular A3A to A3G proteins. These results indicate that A3 proteins are the only essential target of Vif that is required for fully infectious HIV-1 production from THP-1 cells.

Funder

Japan Agency for Medical Research and Development

MEXT | Japan Society for the Promotion of Science

Takeda Science Foundation

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Naito Foundation

Shinnihon Foundation of Advanced Medical Treatment Research

Waksman Foundation of Japan

Canon Foundation in Europe

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

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